tbuckley/cabot-search huggingface dataset:
Patritumab Deruxtecan (HER3-DXd), a Human Epidermal Growth Factor Receptor 3–Directed Antibody-Drug Conjugate, in Patients With Previously Treated Human Epidermal Growth Factor Receptor 3–Expressing Metastatic Breast Cancer: A Multicenter, Phase I/II Trial
Authors: Ian E. Krop, Norikazu Masuda, Toru Mukohara, Shunji Takahashi, Takahiro Nakayama, Kenichi Inoue, Hiroji Iwata, Yutaka Yamamoto, Ricardo H. Alvarez, Tatsuya Toyama, Masato Takahashi, Akihiko Osaki, Shigehira Saji, Yasuaki Sagara, Joyce O'Shaughnessy, Shoichi Ohwada, Kumiko Koyama, Tatsuya Inoue, Li Li, Parul Patel, Joseph Mostillo, Yoshimi Tanaka, David W. Sternberg, Dalila Sellami, Kan Yonemori
Journal: Journal of Clinical Oncology (2023)

Human epidermal growth factor receptor 3 (HER3) is broadly expressed in breast cancer; high expression is associated with an adverse prognosis. Patritumab deruxtecan (HER3-DXd) is an investigational HER3-targeted antibody-drug conjugate that is being evaluated as a novel treatment in HER3-expressing advanced breast cancer in the U31402-A-J101 study.Adults with disease progression on previous therapies were eligible. Patients in the dose-escalation, dose-finding, and dose-expansion parts received HER3-DXd 1.6-8.0 mg/kg intravenously once every 3 weeks or one of two alternative dosing regimens. In the dose-escalation part, the primary objectives were to determine the maximum tolerated dose and recommended dose for expansion (RDE). The safety and efficacy of the RDE were assessed during dose expansion.One hundred eighty-two enrolled patients received ≥1 dose of HER3-DXd. Patients had a median of five previous therapies for advanced disease. Efficacy results are reported across clinical subtypes: hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-negative) breast cancer (n = 113; objective response rate [ORR], 30.1%; median progression-free survival [mPFS], 7.4 months), triple-negative breast cancer (n = 53; ORR, 22.6%; mPFS, 5.5 months), and HER2-positive breast cancer (n = 14; ORR, 42.9%; mPFS, 11.0 months). Objective responses were observed in cancers with HER3-high and HER3-low membrane expression. Dose-limiting toxicities observed during dose selection were decreased platelet count and elevated aminotransferases. In dose expansion, GI and hematologic toxicities were the most common treatment-emergent adverse events (TEAEs) observed. Grade ≥3 TEAEs were observed in 71.4% of patients, and 9.9% discontinued treatment because of TEAEs. Three grade 3 and one grade 5 treatment-related interstitial lung disease events occurred.HER3-DXd demonstrated a manageable safety profile and durable efficacy in heavily pretreated patients across clinical subtypes. These data warrant further evaluation of HER3-DXd in patients with HER3-expressing metastatic breast cancer.
Importance of Low- and Moderate-Grade Adverse Events in Patients' Treatment Experience and Treatment Discontinuation: An Analysis of the E1912 Trial
Authors: Nathaniel S. O'Connell, Fengmin Zhao, Ju-Whei Lee, Edward H. Ip, John Devin Peipert, Noah Graham, Mary Lou Smith, Ilana F. Gareen, Ruth C. Carlos, Samilia Obeng-Gyasi, Joseph A. Sparano, Tait D. Shanafelt, Mary L. Thomas, David Cella, Lynne I. Wagner, Robert Gray
Journal: Journal of Clinical Oncology (2023)

PURPOSE Despite defined grades of 1 to 5 for adverse events (AEs) on the basis of Common Terminology Criteria for Adverse Events criteria, mild (G1) and moderate (G2) AEs are often not reported in phase III trials. This under-reporting may inhibit our ability to understand patient toxicity burden. We analyze the relationship between the grades of AEs experienced with patient side-effect bother and treatment discontinuation . METHODS We analyzed a phase III Eastern Cooperative Oncology Group-American College of Radiology Imaging Network trial with comprehensive AE data. The Likert response Functional Assessment of Cancer Therapy-GP5 item, “I am bothered by side effects of treatment” was used to define side-effect bother. Bayesian mixed models were used to assess the impact of G1 and G2 AE counts on patient side-effect bother and treatment discontinuation. AEs were further analyzed on the basis of symptomatology (symptomatic or asymptomatic). The results are given as odds ratios (ORs) and 95% credible interval (CrI). RESULTS Each additional G1 and G2 AEs experienced during a treatment cycle increased the odds of increased self-reported patient side-effect bother by 13% (95% CrI, 1.06 to 1.21) and 35% (95% CrI, 1.19 to 1.54), respectively. Furthermore, only AEs defined as symptomatic were associated with increased side-effect bother, with asymptomatic AEs showing no association regardless of grade. Count of G2 AEs increased the odds of treatment discontinuation by 59% (95% CrI, 1.32 to 1.95), with symptomatic G2 AEs showing a stronger association (OR, 1.75; 95% CrI, 1.28 to 2.39) relative to asymptomatic G2 AEs (OR, 1.45; 95% CrI, 1.12 to 1.89). CONCLUSION Low- and moderate-grade AEs are related to increased odds of increased patient side-effect bother and treatment discontinuation, with symptomatic AEs demonstrating greater magnitude of association than asymptomatic. Our findings suggest that limiting AE capture to grade 3+ misses important contributors to treatment side-effect bother and discontinuation.
Taking the STING out of CIN
Authors: Anouk van den Brink, Floris Foijer
Journal: Trends in cancer (2023)

Chromosomal instability (CIN), a hallmark of cancer, promotes cell-intrinsic inflammatory signaling. Although inflammation is generally considered tumor-suppressive, this relationship is more complex in cancers with CIN. We discuss new findings by Li et al. that can explain how cancer cells with CIN tolerate, adopt, and rewire the CIN-induced inflammatory response to fuel tumorigenesis.
Comparison of 18F-FDG and 68Ga-FAPI PET/CT in a Patient With Hepatic Perivascular Epithelioid Cell Neoplasm
Authors: Zhuoyuan Li, Dan Su, Sihui Zhou, Yudi Wang, Yue Chen
Journal: Clinical Nuclear Medicine (2023)

The prevalence of hepatic perivascular epithelioid cell neoplasm (PEComa) is extremely low, and imaging diagnosis is very difficult. We presented 18 F-FDG and 68 Ga-FAPI PET/CT findings in a 58-year-old woman with pathologically confirmed hepatic PEComa. The tumor showed intense 68 Ga-FAPI uptake but only mild 18 F-FDG activity on PET/CT studies. This case suggested that 68 Ga-FAPI PET/CT might be a useful tool for evaluation of hepatic PEComa with remarkable tumor-to-liver ratios.
Image-Guided Fine-Needle Aspiration Cytology for BRCA Mutation Assessment of PSMA-Positive Lymph Node Metastases in a Patient With Metastatic Castration-Resistant Prostate Cancer
Authors: Anke Werner, Philipp Seifert, Bernhard Theis, Martin Freesmeyer, Theresa Leder
Journal: Clinical Nuclear Medicine (2023)

A 64-year-old man with metastatic castration-resistant prostate cancer presented for prostate-specific membrane antigen (PSMA) PET/CT in preparation for 177 Lu-PSMA radioligand therapy. For precedent BRCA mutation assessment, fine-needle aspiration cytology of 2 PSMA-positive lymph node metastases was conducted. The acquired material was suitable for next-generation sequencing-based gene panel diagnostics and did not show a BRCA1 / 2 mutation, thus PSMA radioligand therapy was initiated. Fine-needle aspiration cytology of lymph node metastases may be a viable option in evaluating further therapeutic alternatives.
Discordant Uptake of Leg Thrombi Versus Pulmonary Emboli on 68Ga-FAPI-46 PET/CT
Authors: Sang-Geon Cho, Chan Park, Jahae Kim, Kang Bin Kim, Hyung Yoon Kim
Journal: Clinical Nuclear Medicine (2023)

Fibroblast activation protein inhibitor (FAPI) PET is gaining clinical relevance for visualizing activated fibroblasts in various diseases. Here, we report discordant FAPI uptake between venous thrombi of the lower extremities and pulmonary emboli. An 86-year-old man complained of left leg swelling and acute dyspnea; he was diagnosed with deep vein thrombosis involving the left femoral vein and acute pulmonary thromboembolism. Positive FAPI uptake was observed only in the thrombi of the left femoral vein, but not in the pulmonary emboli. Such discrepancies may indicate different thrombus constituents and chronologies even in the same patient.
Whole-Body 18F-FDG PET/CT Patlak Parametric Imaging of Hepatic Alveolar Echinococcosis
Authors: Alexander Maurer, Fotis Kotasidis, Ansgar Deibel, Irene A. Burger, Martin W. Huellner
Journal: Clinical Nuclear Medicine (2023)

We present dynamic 18 F-FDG PET/CT acquisition in a 52-year-old old woman with histologically proven hepatic alveolar echinococcosis (AE). Metabolic rate of FDG images generated with traditional and relative Patlak analysis show the AE manifestation in the liver significantly better the static SUV images. Dynamic PET may thus have the potential to increase sensitivity in the assessment of hepatic AE manifestations. Such parametric images may offer complementary qualitative information and quantification superior to SUV images.
False-Positive 131I Uptake After Posttraumatic Scab in a Patient With Papillary Thyroid Carcinoma
Authors: Jun Yang, Pingping Zhou, Xinhui Su
Journal: Clinical Nuclear Medicine (2023)

A 41-year-old woman with right papillary thyroid carcinoma underwent 131 I therapy (3.7 GBq). Posttherapy whole-body scintigraphy acquired 2 days later revealed a focus of intense activity in the anterior aspect of the left knee. The activity corresponding to the posttraumatic scab. Posttraumatic scab should be considerable a cause of false-positive whole-body scintigraphy findings.
Prostate Cancer Progression Relies on the Mitotic Kinase Citron Kinase
Authors: Chitra Rawat, Salma Ben-Salem, Nidhi Singh, Gaurav Chauhan, Anja Rabljenovic, Vishwa Vaghela, Varadha Balaji Venkadakrishnan, Jonathan D. Macdonald, Ujjwal R. Dahiya, Yara Ghanem, Salam Bachour, Yixue Su, Adam D. DePriest, Sanghee Lee, Michelle Muldong, Hyun-Tae Kim, Sangeeta Kumari, Malyn May Valenzuela, Dingxiao Zhang, Qiang Hu, Eduardo Cortes Gomez, Scott M. Dehm, Amina Zoubeidi, Christina A.M. Jamieson, Marlo Nicolas, Jesse McKenney, Belinda Willard, Eric A. Klein, Cristina Magi-Galluzzi, Shaun R. Stauffer, Song Liu, Hannelore V. Heemers
Journal: Cancer Research (2023)

Abstract Prostate cancer remains the second leading cause of cancer death in men in Western cultures. A deeper understanding of the mechanisms by which prostate cancer cells divide to support tumor growth could help devise strategies to overcome treatment resistance and improve survival. Here, we identified that the mitotic AGC family protein kinase citron kinase (CIT) is a pivotal regulator of prostate cancer growth that mediates prostate cancer cell interphase progression. Increased CIT expression correlated with prostate cancer growth induction and aggressive prostate cancer progression, and CIT was overexpressed in prostate cancer compared with benign prostate tissue. CIT overexpression was controlled by an E2F2–Skp2–p27 signaling axis and conferred resistance to androgen-targeted treatment strategies. The effects of CIT relied entirely on its kinase activity. Conversely, CIT silencing inhibited the growth of cell lines and xenografts representing different stages of prostate cancer progression and treatment resistance but did not affect benign epithelial prostate cells or nonprostatic normal cells, indicating a potential therapeutic window for CIT inhibition. CIT kinase activity was identified as druggable and was potently inhibited by the multikinase inhibitor OTS-167, which decreased the proliferation of treatment-resistant prostate cancer cells and patient-derived organoids. Isolation of the in vivo CIT substrates identified proteins involved in diverse cellular functions ranging from proliferation to alternative splicing events that are enriched in treatment-resistant prostate cancer. These findings provide insights into the regulation of aggressive prostate cancer cell behavior by CIT and identify CIT as a functionally diverse and druggable driver of prostate cancer progression. Significance: The poorly characterized protein kinase citron kinase is a therapeutic target in prostate cancer that drives tumor growth by regulating diverse substrates, which control several hallmarks of aggressive prostate cancer progression. See related commentary by Mishra et al., p. 4008
XPO1 Enables Adaptive Regulation of mRNA Export Required for Genotoxic Stress Tolerance in Cancer Cells
Authors: Rossella Marullo, Sarah C. Rutherford, Maria V. Revuelta, Nahuel Zamponi, Biljana Culjkovic-Kraljacic, Nikita Kotlov, Nicolás Di Siervi, Juan Lara-Garcia, John N. Allan, Jia Ruan, Richard R. Furman, Zhengming Chen, Tsiporah B. Shore, Adrienne A. Phillips, Sebastian Mayer, Jingmei Hsu, Koen van Besien, John P. Leonard, Katherine L.B. Borden, Giorgio Inghirami, Peter Martin, Leandro Cerchietti
Journal: Cancer Research (2023)

Abstract Exportin-1 (XPO1), the main soluble nuclear export receptor in eukaryotic cells, is frequently overexpressed in diffuse large B-cell lymphoma (DLBCL). A selective XPO1 inhibitor, selinexor, received approval as single agent for relapsed or refractory (R/R) DLBCL. Elucidating the mechanisms by which XPO1 overexpression supports cancer cells could facilitate further clinical development of XPO1 inhibitors. We uncovered here that XPO1 overexpression increases tolerance to genotoxic stress, leading to a poor response to chemoimmunotherapy. Upon DNA damage induced by MYC expression or exogenous compounds, XPO1 bound and exported EIF4E and THOC4 carrying DNA damage repair mRNAs, thereby increasing synthesis of DNA damage repair proteins under conditions of increased turnover. Consequently, XPO1 inhibition decreased the capacity of lymphoma cells to repair DNA damage and ultimately resulted in increased cytotoxicity. In a phase I clinical trial conducted in R/R DLBCL, the combination of selinexor with second-line chemoimmunotherapy was tolerated with early indication of efficacy. Overall, this study reveals that XPO1 overexpression plays a critical role in the increased tolerance of cancer cells to DNA damage while providing new insights to optimize the clinical development of XPO1 inhibitors. Significance: XPO1 regulates the dynamic ribonucleoprotein nuclear export in response to genotoxic stress to support tolerance and can be targeted to enhance the sensitivity of cancer cells to endogenous and exogenous DNA damage. See related commentary by Knittel and Reinhardt, p. 3
Pan American League of Associations for Rheumatology recommendations for the management of axial spondyloarthritis
Authors: Wilson Bautista-Molano, Daniel G. Fernández-Ávila, María Lorena Brance, María Gabriela Ávila Pedretti, Ruben Burgos-Vargas, Inés Corbacho, Vanesa Laura Cosentino, José Francisco Díaz Coto, Enrique Giraldo Ho, Gustavo Gomes Resende, Luis Arturo Gutiérrez, Marwin Gutiérrez, Sebastián Eduardo Ibáñez Vodnizza, Edwin Jáuregui, Vanessa Ocampo, Daniel Ruben Palleiro Rivero, Penélope Esther Palominos, Cesar Pacheco Tena, Guillermo Andrés Quiceno, Lina María Saldarriaga-Rivera, Fernando Andrés Sommerfleck, Annelise Goecke Sariego, Claudia Vera Barrezueta, Luis Enrique Vega Espinoza, Oscar Vega Hinojosa, Gustavo Citera, Carlos Lozada, Percival D. Sampaio-Barros, Emilce Schneeberger, Enrique R. Soriano
Journal: Nature Reviews Rheumatology (2023)
Double‐strand DNA break repair: molecular mechanisms and therapeutic targets
Authors: Jinpeng Tan, Xingyao Sun, Hongling Zhao, Hua Guan, Shanshan Gao, Ping‐Kun Zhou
Journal: MedComm (2023)

Abstract Double‐strand break (DSB), a significant DNA damage brought on by ionizing radiation, acts as an initiating signal in tumor radiotherapy, causing cancer cells death. The two primary pathways for DNA DSB repair in mammalian cells are nonhomologous end joining (NHEJ) and homologous recombination (HR), which cooperate and compete with one another to achieve effective repair. The DSB repair mechanism depends on numerous regulatory variables. DSB recognition and the recruitment of DNA repair components, for instance, depend on the MRE11–RAD50–NBS1 (MRN) complex and the Ku70/80 heterodimer/DNA–PKcs (DNA–PK) complex, whose control is crucial in determining the DSB repair pathway choice and efficiency of HR and NHEJ. In‐depth elucidation on the DSB repair pathway's molecular mechanisms has greatly facilitated for creation of repair proteins or pathways‐specific inhibitors to advance precise cancer therapy and boost the effectiveness of cancer radiotherapy. The architectures, roles, molecular processes, and inhibitors of significant target proteins in the DSB repair pathways are reviewed in this article. The strategy and application in cancer therapy are also discussed based on the advancement of inhibitors targeted DSB damage response and repair proteins.
Tissue‐type plasminogen activator (tPA) homozygous Tyr471His mutation associates with thromboembolic disease
Authors: Yanyi Tao, Jiewen Ma, Yuanzheng Feng, Chenggang Gao, Tingting Wu, Yunqing Xia, Zhipeng Cheng, Yi Zhang, Tingting Liu, Yu Hu, Liang V. Tang
Journal: MedComm (2023)

Abstract Tissue‐type plasminogen activator (tPA) encoded by PLAT is a major mediator that promotes fibrinolysis and prevents thrombosis. Pathogenetic mutations in PLAT associated with venous thromboembolism have rarely been reported. Here, we report the first case of a homozygous point mutation c.1411T&gt;C (p.Y471H) in PLAT leading to thromboembolic events and conduct related functional studies. The corresponding tPA mutant protein (tPA‐Y471H) and wild‐type tPA (tPA‐WT) were synthesized in vitro, and mutant mice ( PLAT H/H mice) were constructed. The molecular docking and surface plasmon resonance results indicated that the mutation impeded the hydrogen‐bonding interactions between the protease domain of tPA and the kringle 4 domain of plasminogen, and the binding affinity of tPA and plasminogen was significantly reduced with a difference of one order of magnitude. mRNA half‐life assay showed that the half‐life of tPA‐Y471H was shortened. The inferior vena cava thrombosis model showed that the rate of venous thrombosis in PLAT H/H mice was 80% compared with 53% in wild‐type mice. Our data suggested a novel role for the protease domain of tPA in efficient plasminogen activation, and demonstrated that this tPA mutation could reduce the fibrinolysis function of the body and lead to an increased propensity for thrombosis.
Single‐cell RNA sequencing reveals the effects of capsaicin in the treatment of sepsis‐induced liver injury
Authors: Qian Zhang, Jing Liu, Jing Shen, Jinhuan Ou, Yin Kwan Wong, Lulin Xie, Jingnan Huang, Chunting Zhang, Chunjin Fu, Junhui Chen, Jiayun Chen, Xueling He, Fei Shi, Piao Luo, Ping Gong, Xueyan Liu, Jigang Wang
Journal: MedComm (2023)

Sepsis is a difficult-to-treat systemic condition in which liver dysfunction acts as both regulator and target. However, the dynamic response of diverse intrahepatic cells to sepsis remains poorly characterized. Capsaicin (CAP), a multifunctional chemical derived from chilli peppers, has recently been shown to potentially possess anti-inflammatory effects, which is also one of the main approaches for drug discovery against sepsis. We performed single-cell RNA transcriptome sequencing on 86,830 intrahepatic cells isolated from normal mice, cecal ligation and puncture-induced sepsis model mice and CAP-treated mice. The transcriptional atlas of these cells revealed dynamic changes in hepatocytes, macrophages, neutrophils, and endothelial cells in response to sepsis. Among the extensive crosstalk across these major subtypes, KC_Cxcl10 shared strong potential interaction with other cells when responding to sepsis. CAP mitigated the severity of inflammation by partly reversing these pathophysiologic processes. Specific cell subpopulations in the liver act collectively to escalate inflammation, ultimately causing liver dysfunction. CAP displays its health-promoting function by ameliorating liver dysfunction induced by sepsis. Our study provides valuable insights into the pathophysiology of sepsis and suggestions for future therapeutic gain.
“Enough is Enough”: tackling sexism, sexual harassment, and power abuse in Spain's academia and healthcare sector
Authors: Blanca Paniello-Castillo, Elena González-Rojo, Thaïs González-Capella, Neus Rosell Civit, Ana Bernal-Triviño, Helena Legido-Quigley, Montserrat Gea-Sánchez
Journal: The Lancet Regional Health - Europe (2023)
Measuring people’s views on health system performance: Design and development of the People’s Voice Survey
Authors: Todd P. Lewis, Neena R. Kapoor, Amit Aryal, Rodrigo Bazua-Lobato, Susanne Carai, Emma Clarke-Deelder, Kevin Croke, Rashmi Dayalu, Laura Espinoza-Pajuelo, Günther Fink, Patricia J. Garcia, Ezequiel Garcia-Elorrio, Theodros Getachew, Prashant Jarhyan, Munir Kassa, Soon Ae Kim, Agustina Mazzoni, Jesus Medina-Ranilla, Sailesh Mohan, Gebeyaw Molla, Mosa Moshabela, Inbarani Naidoo, Jacinta Nzinga, Juhwan Oh, Emelda A. Okiro, Dorairaj Prabhakaran, Javier Roberti, Gillian SteelFisher, Tefera Taddele, Ashenif Tadele, Xiaohui Wang, Roman Xu, Hannah H. Leslie, Margaret E. Kruk
Journal: PLoS Medicine (2023)

People should be at the center of health system performance assessment.Populations can provide critical insight on quality of care, confidence in health services, and health outcomes.• However, today's measurement approaches overlook key dimensions of population perspective such as confidence in the health system.Surveys are rarely standardized to enable cross-country comparison.
Health System–Provided Rideshare Is Safe and Addresses Barriers to Colonoscopy Completion
Authors: Rachel B. Issaka, Ari Bell-Brown, Talor Hopkins, Lisa D. Chew, Lisa L. Strate, Bryan J. Weiner, Bryan L. Balmadrid, Lara Hirayama, John M. Inadomi, Scott D. Ramsey, Melora Riveira, Cyndy R. Snyder
Journal: Clinical Gastroenterology and Hepatology (2023)

In 2019, nearly 14 million colonoscopies were performed in the United States.1 In these settings, the accepted practice is that a responsible person drives and chaperones patients home after receiving procedural sedation, including colonoscopy.2 Lack of access to transportation and/or a chaperone is a persistent barrier to care in safety-net health systems and federally qualified health centers as a result of lower incomes, underinsurance, and higher social needs.3 Given racial, ethnic, and socioeconomic disparities in many digestive diseases that require colonoscopy for diagnosis and management, innovative solutions are needed to overcome logistical barriers to colonoscopy completion, especially in these settings.
Genetic architecture of the acute and persistent immune cell response after radiation exposure
Authors: Li He, Chenhan Zhong, Hang Chang, Jamie L. Inman, Susan E. Celniker, Myrsini Ioakeim-Ioannidou, Kevin X. Liu, Daphne Haas-Kogan, Shannon M. MacDonald, David W. Threadgill, Scott C. Kogan, Jian-Hua Mao, Antoine M. Snijders
Journal: Cell Genomics (2023)

Hematologic toxicity is a common side effect of multimodal cancer therapy. Nearly all animal studies investigating the causes of radiotherapy-induced hematologic toxicity use inbred strains with limited genetic diversity and do not reflect the diverse responses observed in humans. We used the population-based Collaborative Cross (CC) mouse resource to investigate the genetic architecture of the acute and persistent immune response after radiation exposure by measuring 22 immune parameters in 1,720 CC mice representing 35 strains. We determined relative acute and persistent radiation resistance scores at the individual strain level considering contributions from all immune parameters. Genome-wide association analysis identified quantitative trait loci associated with baseline and radiation responses. A cross-species radiation resistance score predicted recurrence-free survival in medulloblastoma patients. We present a community resource of immune parameters and genome-wide association analyses before and after radiation exposure for future investigations of the contributions of host genetics on radiosensitivity.